Despite highly encouraging preclinical results, major obstacles remain in the effective clinical combination of antiangiogenic and conventional therapies. Perhaps the most glaring deficiency in scheduling such combinations is a lack of fundamental information regarding alterations in tumor microregional pathophysiol- ogy during treatment. Recent reports have suggested two disparate mechanisms to explain the synergistic benefits of combination therapies: 1) tumor vessels are specifically targeted and disrupted, or 2) vascular functionality is instead enhanced, via vessel normalization. Because radiotherapy (RT) is inherently sensitive to changes in the pathophysiology of the tumor microenvironment, we propose to delineate temporal and spatial variations in tumor oxygenation and vascular function in relation to outcome. Using contrast enhanced MRI indices related to tumor blood flow, Specific Aim 1 will monitor temporal response to fractionated RT and/or various developmental multi-targeted receptor inhibitors from Pfizer Global Research and ImClone Systems. In Specific Aim 2, image processing techniques utilizing images from multiply immunostained frozen tumor sections will further detail microregional heterogeneities in vasculature, perfusion, and oxygenation. Specific Aim 3 will address the question of whether treatment response is enhanced when combination therapies are optimally scheduled to take advantage of predicted alterations in tumor oxygenation or blood flow. Lastly, Specific Aim 4 will correlate MRI, immunohistochemistry, and cytokine/receptor levels to define the mechanistic basis for tumor response and for synergism between antiangiogenic agents and fractionated RT. All aims will further profile "responders" and "nonresponders" to single and combination therapies in terms of pre- and post-therapy pathophysiological and molecular profiles, with the future aim of devising prognostic indicators of tumor response. These results with lead to the more rational and optimal design of effective combined therapies, thereby ultimately accelerating their implementation into clinical protocols.